In many pathological disease processes, the material properties of tissue are altered from a normal state. The development of techniques to measure the mechanical or material properties of tissue can potentially facilitate disease diagnosis and guidance of therapy. The system and methods described in this embodiment can potentially be applied for diagnosis of a variety of disease processes. To describe the technique, in this embodiment it is possible to focus on the cardiovascular applications for the detection of unstable atherosclerotic plaque.
Atherosclerotic Plaque Rupture and the Role of Biomechanical Factors: Despite widespread efforts towards its detection and therapy, thrombus mediated ischemic cardiovascular disease still remains the leading cause of mortality in industrialized societies. The rupture of unstable coronary atherosclerotic plaque frequently can precede a majority of ischemic cardiovascular events. The mechanisms leading to plaque rupture can be multi-factorial involving a complex liaison between morphological, compositional, biochemical and biomechanical processes. Due to the cumulative effect of multiple factors, the mechanical stability of the plaque is compromised resulting in an elevated risk of rupture. It is believed that during atherosclerotic plaque progression, the intrinsic mechanical properties of the plaque are serially altered and the measurement of a metric to accurately evaluate intrinsic plaque mechanical properties provides a key determinant of plaque stability. This belief can be based on evidence that mechanical factors greatly influence plaque stability. Hemodynamic forces affect wall shear stresses influencing plaque progression, susceptibility to plaque rupture and coronary thrombosis.6 Finite element studies have suggested that rupture of the fibrous cap is greatly influenced by regions of high circumferential stress typically in the lateral cap shoulders. The morphology and mechanical properties of the atheroma can affect stress distributions, with plaque rupture frequently occurring in focal regions of high stress concentrations caused by large differences in intrinsic mechanical properties of the fibrous cap and lipid pool. The mechanical properties of the atheroma determine the extent of induced deformation or strain in response to an extrinsic load. Higher strains are measured in lipid rich regions of lower viscosity. Cyclic mechanical strain within the arterial wall affects macrophage gene expression and SMC proliferation. Histology studies have shown the localization of MMP-1 in regions of high circumferential strain within plaques, suggesting that mechanical properties influence MMP release further weakening plaque structure contributing to a greater tendency towards plaque rupture.
Image-based methods to measure arterial mechanical properties: A variety of techniques such as intravascular ultrasound (IVUS), virtual histology (VH)-IVUS, magnetic resonance imaging (MRI), angioscopy, thermography, near infrared (NIR) and Raman spectroscopy have been investigated for evaluating coronary plaques in patients. High resolution optical techniques such as optical coherence tomography (OCT) and its next generation implementation, optical frequency domain imaging (OFDI) can provide the opportunity to evaluate plaque microstructure and identify TCFA's in patients. These technologies provide invaluable information on microstructural, compositional and inflammatory factors related to plaque instability and are complementary to approaches that measure mechanical factors. To address the specific need for evaluating mechanical factors, IVUS elastography and finite element analysis (FEA) techniques have been developed. IVUS elastography computes local strains in the arterial wall in response to intra-luminal pressure differentials using cross-correlation analysis and estimation of tissue velocity gradients. Elastography approaches have been applied to OCT to potentially provide higher spatial resolution of strain estimation relative to IVUS. FEA approaches can utilize computer-generated models based on OCT or IVUS cross-sections and estimates of tissue material properties for modeling intra-plaque stress/strain distributions. These techniques provide important information in that they enable the measurement of plaque response to a dynamic external loading environment, thus aiding the investigation of plaque instability. However, the measurement of plaque viscoelasticity using these approaches is intractable, requiring a priori guesstimates of viscoelastic properties, and knowledge of microstructure and loading conditions to solve the inverse problem.
Viscoelasticity and Brownian Motion: Tissue is viscoelastic in nature, exhibiting both solid and fluid like characteristics. The mechanical properties of viscoelastic materials can be evaluated by measuring a quantity, termed the “viscoelastic modulus”, which determines the strain induced in the material in response to an extrinsic load. Traditionally, the viscoelastic modulus is measured using a mechanical rheometer, in which a material is loaded between two parallel plates, an oscillatory stress at frequency, ω, is applied and the a strain response is measured to evaluate viscoelasticity. The measured viscoelastic modulus, G*(ω), is expressed as, G*(ω)=G′(ω)+iG″(ω). The real part, G′(ω), is the elastic modulus which defines the elastic solid like characteristics of the material and is the ratio of the elastic component of the oscillatory stress which is in phase with the strain. The imaginary part, G″(ω), provides the viscous modulus and measures the out-of-phase response of the medium defining the material's fluid like characteristics. The ratio between the elastic to viscous moduli provides a measure of ‘phase’, where a lower phase represents a more elastically dominated and a higher phase represents a more viscously dominated material.
Studies in the field of polymer rheology have demonstrated non-contact approaches to measure the viscoelastic modulus by evaluating the passive movements (Brownian motion) of particles suspended in a viscoelastic medium. In one publication, it was demonstrated that the Brownian motion of suspended particles is intimately related to the structure and viscoelastic properties of the suspending medium, and particles exhibit larger range of motions when their local environment is less rigid. This indicated that the response of a viscoelastic material to the average Brownian motion of dispersed microscopic particles closely resembles the response of the material to an imposed oscillatory mechanical load at frequency, ω. Consequently, other studies have indicated the use of light scattering techniques to evaluate the viscoelastic modulus of homogenous polymer materials by suspending exogenous particles and measuring the time scale and mean square displacement of microscopic trajectories. By applying these concepts, a further exemplary optical technique can be reviewed, e.g., termed Laser Speckle Imaging, which analyzes the intrinsic Brownian motion of endogenous microscopic light scattering particles that are inherently present within tissue to evaluate tissue viscoelasticity.
Laser Speckle Imaging (LSI): When an object is imaged using highly coherent light from a laser, a granular pattern of multiple bright and dark spots becomes apparent on the image, which bears no perceptible relationship to the macroscopic structure of the object. These random intensity patterns, termed as laser speckle, can occur in two situations: (i) when coherent light is reflected from a surface which is rough on the scale of an optical wavelength, and (ii) when coherent light propagates through and is scattered by a medium with random refractive index fluctuations such as in tissue. The interference of light returning from the random surface or medium causes laser speckle. Laser speckle formed from scattering within tissue is exquisitely sensitive to Brownian motion. The Brownian motion of endogenous light scattering particles in tissue causes scatterer locations and optical path lengths to dynamically change resulting in time dependent intensity modulations of laser speckle. The rate of laser speckle modulation can be highly dependent on the extent of motion of suspended scatterers, which is in turn influenced by viscoelasticity of the medium. Consequently, in an atheroma, due to the relatively low viscosity of lipid, endogenous scatterers within the compliant necrotic core exhibit more rapid Brownian motion compared to the stiffer fibrous regions of the plaque. Since scatterer motion governs the modulation of laser speckle, the measurement of temporal intensity variations of laser speckle patterns provides information about the viscoelastic properties of the plaque. Using these principles, the measurement of intensity modulations of time-varying laser speckle patterns can provide a highly sensitive technique for evaluating atherosclerotic plaques. Exemplary procedures using excised atherosclerotic plaques have been reviewed, indicating that the measurement of intrinsic Brownian motion of endogenous particles, related to viscoelasticity, can be used to distinguish plaque type, and evaluate collagen and lipid content.